Prescription opioid misuse and abuse are increasing problems in the United States. In the 2006 National Survey on Drug Use and Health, 5.2 million Americans had illicitly used a prescription opioid in the past month. National rates of illicit prescription opioid use are higher than those for heroin, cocaine or methamphetamine and are exceeded only by marijuana. Moreover, the number of individuals initiating illicit use of prescription opioids was greater than that for marijuana in 2004 and 2005. These findings indicate that illicit prescription opioid use represents a significant public health concern greater than that of cocaine, heroin or methamphetamine and perhaps approaching that of marijuana. The increase in illicit prescription opioid use may be due to increased availability of opioid analgesics medications with significant abuse potential. Discovery and development of opioid analgesics with reduced abuse potential may serve to decrease prescription opioid misuse and the subsequent development of opioid use disorders. Tramadol is an unscheduled atypical analgesic with opioid activity. While rare cases of tramadol abuse and physical dependence have been reported, it has reduced abuse potential relative to typical prescription opioids. The reduced abuse potential of tramadol has been attributed to its novel pharmacology. Tramadol is a mu opioid agonist, but also blocks reuptake of serotonin and norepinephrine. The specific aim of the present application is to elucidate the relative contributions of mu opioid, serotonin and norepinephrine receptor systems to the effects of tramadol using an array of pharmacologic measures relevant to its abuse potential and analgesic efficacy in human volunteers. The knowledge gained about tramadol from the proposed experiments in terms of its neuropharmacology will aid in the discovery and development of other opioid medications with reduced abuse potential. Specifically, if the non-mu mediated effects of tramadol contribute to its analgesic efficacy and reduced abuse potential, these findings would support the development of other analgesics with similar neuropharmacological mechanisms. This project will employ placebo-controlled, randomized and double blind testing procedures to evaluate the behavioral effects of tramadol across three experiments. Overall, this project will contribute important clinical information regarding the pharmacology of tramadol in relation to its analgesic efficacy and reduced abuse potential and provide basic science information about the behavioral effects of prescription opioids in humans. PUBLIC HEALTH RELEVANCE: The research proposed in this application seeks to understand better the human neuropharmacology of tramadol, an atypical analgesic with opioid action that has reduced abuse potential relative to other opioid analgesics. We are seeking to understand how the neuropharmacology of tramadol influences both its analgesic efficacy and reduced abuse potential in an effort to aid development of other analgesic medications with reduced abuse potential. Developing analgesics with reduced abuse potential may reduce the prevalence of prescription opioid misuse and subsequent opioid use disorders.